Cancer is a disease characterised by new and abnormal growth of cells within an individual. Cancer develops through a multi-step process involving several mutational events that allow cancer cells to develop, that is to say cells which display the properties of invasion and metastasis. Generally speaking, there are two classes of genes in which mutation can occur and give rise to cancer: oncogenes and tumour suppressor genes. The activation of oncogenes gives rise to new properties of the cell such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries and the ability to become established in diverse tissue environments. Tumour suppressor genes can be inactivated which permits the loss of normal functions in the cell such as accurate DNA replication, control over the cell cycle, orientation, and adhesion within tissues and interaction with protective cells of the immune system.
Numerous approaches have been proposed for the treatment and prophylaxis of cancer. One approach is the use of antigenic peptides which comprise fragments of tumour specific antigens. Such antigenic peptides, when administered to an individual, elicit an MHC class I or class II restricted T-cell response against cells expressing the tumour specific antigens.
It is to be appreciated that in order for such a T-cell response to occur, the antigenic polypeptide must be presented on an MHC molecule. There is a wide range of variability in MHC molecules in human populations. In particular, different individuals have different HLA alleles which have varying binding affinity for polypeptides, depending on the amino acid sequence of the polypeptides. Thus an individual who has one particular HLA allele may have MHC molecules that will bind a polypeptide of a particular sequence whereas other individuals lacking the HLA allele will have MHC molecules unable to bind and present the polypeptide (or, at least, their MHC molecules will have a very low affinity for the polypeptide and so present it at a relatively low level).
It has also been proposed to provide a vaccine comprising a nucleic acid molecule that encodes such an antigenic peptide. Such a vaccine operates by way of a similar principle except that after administration of the vaccine to an individual in need of treatment, the nucleic acid molecule is transcribed (if it is DNA molecule) and translated in order to synthesise the peptide which is then bound and presented by an MHC molecule as described above.
Telomerase is an enzyme that has the function of replicating the 3′ end of the telomerase regions of linear DNA strands in eukaryotic cells as these regions cannot be extended by the enzyme DNA polymerase in the normal way. The telomerase enzyme comprises a telomerase reverse transcriptase subunit (“TERT” or “hTERT” for humans) and telomerase RNA. By using the telomerase RNA as a template, the telomerase reverse transcriptase subunit adds a repeating sequence to the 3′ end of chromosomes in eukaryotic cells in order to extend the 3′ end of the DNA strand.
It has been observed that the telomerase enzyme is activated in the vast majority of all human tumours. It is believed that this occurs because, without the expression of the telomerase enzyme, the telomeres of cells are gradually lost, and the integrity of the chromosomes decline with each round of cell division of a cell which ultimately results in apoptosis of the cells. Thus, expression of the telomerase enzyme is generally necessary for a cancer cell to develop because without such expression, programmed cell death will usually occur by default. In view of the role of telomerase activation in cancer, telomerase has been regarded as a tumour specific antigen and thus as a potential target for cancer therapy.
WO03/038047 discloses a peptide designated as T672 which is reported to elicit a proliferative T-cell response from cells of healthy donors. Various other peptides of hTERT are also disclosed but were not subject to any experimental testing.
WO00/02581 discloses polypeptides of telomerase which elicit an MHC class I and/or class II restricted T-cell response. One of the polypeptides disclosed (having the amino acid sequence EARPALLTSRLRFIPK, which is also known as GV1001) is undergoing a phase III clinical trial (Telo Vac) in the UK in pancreatic cancer patients as a vaccine treatment.
WO02/094312 discloses certain polypeptides derived from hTERT.
Liu J P et al (2009 Telomerase in cancer immunotherapy Biochim Biophys Acta. September 12) reviewed 26 hTERT peptides that had been shown to induce efficient immune responses to hTERT positive tumour cells.
Dendritic cells transfected with hTERT mRNA have also previously been employed to treat metastatic prostate cancer patients (Su et al, 2005, Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol. 174(6):3798-807). Su et al demonstrated successful generation of hTERT-specific T cell responses measured as IFNγ secreting CD8+ T cells and CTL-mediated killing of hTERT targets. Four patients also experienced partial clinical responses. However, no hTERT epitopes were characterized in these studies.
There is always a need for further antigenic polypeptides (and nucleic acid molecules which encode such polypeptides) for the treatment of cancer, such as polypeptides which can elicit a more effective immune response in individuals and/or polypeptides which are presented by HLA alleles present in a greater proportion of the population.
The present seeks to alleviate one or more of the above problems.